2022
Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis
LaMoia TE, Butrico GM, Kalpage HA, Goedeke L, Hubbard BT, Vatner DF, Gaspar RC, Zhang XM, Cline GW, Nakahara K, Woo S, Shimada A, Hüttemann M, Shulman GI. Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2122287119. PMID: 35238637, PMCID: PMC8916010, DOI: 10.1073/pnas.2122287119.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectPlasma glucose concentrationComplex I activityHepatic gluconeogenesisType 2 diabetes mellitusGlucose concentrationGlycerol-3-phosphate dehydrogenase activityI activityDiabetes mellitusSelective inhibitionMetforminInhibitionRelevant concentrationsGluconeogenesisPhenforminVivoMost studiesDehydrogenase activityGalegineMellitus
2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationMechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice
Li X, Zhang D, Vatner DF, Goedeke L, Hirabara SM, Zhang Y, Perry RJ, Shulman GI. Mechanisms by which adiponectin reverses high fat diet-induced insulin resistance in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 32584-32593. PMID: 33293421, PMCID: PMC7768680, DOI: 10.1073/pnas.1922169117.Peer-Reviewed Original ResearchConceptsEpididymal white adipose tissueInsulin resistanceAdiponectin treatmentAdipose tissueHigh-fat diet-induced insulin resistanceType 2 diabetes mellitusWhole-body insulin resistanceDiet-induced insulin resistanceSkeletal muscleEctopic lipid storageReverses insulin resistanceInsulin-mediated suppressionMuscle fatty acid oxidationEndogenous glucose productionMuscle insulin resistanceWhite adipose tissueLipoprotein lipase activityMuscle fat oxidationPKCε translocationInsulin-stimulated glucose uptakeFatty acid oxidationTAG uptakeDiabetes mellitusMuscle sensitivityAkt serine phosphorylationNon‐alcoholic Fatty Liver Disease and Insulin Resistance
Petersen M, Samuel V, Petersen K, Shulman G. Non‐alcoholic Fatty Liver Disease and Insulin Resistance. 2020, 455-471. DOI: 10.1002/9781119436812.ch37.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseHepatic insulin resistanceFatty liver diseaseInsulin resistanceLiver diseaseDevelopment of NAFLDLipid-induced muscle insulin resistanceRandle glucose-fatty acid cycleCommon chronic liver diseaseType 2 diabetes mellitusHyperinsulinemic-euglycemic clamp studiesGlucose-fatty acid cycleLiver-related deathSkeletal muscleChronic liver diseaseNon-alcoholic steatohepatitisMajor risk factorLipid-induced hepatic insulin resistanceMuscle insulin resistanceDiabetes mellitusRisk factorsClamp studiesLipoprotein lipaseDiseaseProtein kinase C
2001
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim J, Fillmore J, Chen Y, Yu C, Moore I, Pypaert M, Lutz E, Kako Y, Velez-Carrasco W, Goldberg I, Breslow J, Shulman G. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 7522-7527. PMID: 11390966, PMCID: PMC34701, DOI: 10.1073/pnas.121164498.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseFatty Acids, NonesterifiedGlucagonGlucoseGlucose Clamp TechniqueGlucose Tolerance TestHeterozygoteInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLeptinLipoprotein LipaseLiverMiceMice, KnockoutMice, TransgenicMuscle, SkeletalOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphoproteinsSignal TransductionTriglyceridesConceptsInsulin resistanceFatty acid-derived metabolitesInsulin actionTriglyceride contentType 2 diabetes mellitusInsulin activationLipoprotein lipaseInsulin receptor substrate-1-associated phosphatidylinositolMuscle triglyceride contentSkeletal muscleTissue-specific insulin resistanceLiver triglyceride contentAdipocyte-derived hormoneHyperinsulinemic-euglycemic clampEndogenous glucose productionLiver-specific overexpressionTissue-specific overexpressionInsulin-stimulated glucose uptakeDiabetes mellitusTissue-specific increaseTransgenic miceGlucose productionFat metabolismGlucose uptakeInsulin
1999
Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes
Cline G, Petersen K, Krssak M, Shen J, Hundal R, Trajanoski Z, Inzucchi S, Dresner A, Rothman D, Shulman G. Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes. New England Journal Of Medicine 1999, 341: 240-246. PMID: 10413736, DOI: 10.1056/nejm199907223410404.Peer-Reviewed Original ResearchConceptsMuscle glycogen synthesisType 2 diabetes mellitusConcentrations of insulinNormal subjectsDiabetes mellitusGlucose metabolismGlycogen synthesisGlucose concentrationWhole-body glucose metabolismInsulin-stimulated muscle glycogen synthesisIntracellular glucose concentrationType 2 diabetesPlasma insulin concentrationGlucose transportImpaired glucose transportInterstitial fluid glucose concentrationsOpen-flow microperfusionIntramuscular glucoseInterstitial fluidGlucose-6-phosphate concentrationInsulin resistanceVivo microdialysisInsulin concentrationsHyperinsulinemic conditionsPatients
1998
Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus
Inzucchi S, Maggs D, Spollett G, Page S, Rife F, Walton V, Shulman G. Efficacy and Metabolic Effects of Metformin and Troglitazone in Type II Diabetes Mellitus. New England Journal Of Medicine 1998, 338: 867-873. PMID: 9516221, DOI: 10.1056/nejm199803263381303.Peer-Reviewed Original ResearchConceptsEndogenous glucose productionPlasma glucose concentrationPostprandial plasma glucose concentrationsPeripheral glucose disposalType 2 diabetesMetformin therapyTroglitazone therapyGlucose disposalGlucose productionHemoglobin valuesGlucose concentrationType II diabetes mellitusAdditive beneficial effectsSingle-drug therapyDiabetes mellitusGlycemic controlCombination therapyPoor responseMetabolic effectsPhysiologic effectsMetforminPatientsTherapyTroglitazoneBeneficial effects
1996
Time course of the defective α-cell response to hypoglycemia in diabetic BB rats
Jacob R, Dziura J, Morgen J, Shulman G, Sherwin R. Time course of the defective α-cell response to hypoglycemia in diabetic BB rats. Metabolism 1996, 45: 1422-1426. PMID: 8931649, DOI: 10.1016/s0026-0495(96)90125-0.Peer-Reviewed Original ResearchConceptsInsulin-dependent diabetes mellitusDays of diabetesBB ratsBB/Wor ratsNondiabetic BB ratsΑ-cell responseDiabetic BB ratsCourse of diabetesPancreatic glucagon levelsPancreatic glucagon contentBeta-cell functionPancreatic insulin contentHypoglycemic challengeCounterregulatory responsesDiabetes onsetDiabetes mellitusGlucagon levelsGlucagon releasePlasma glucagonGlucagon concentrationsInsulin clampGlucagon contentBaseline plasmaDisease onsetGroup 2
1990
Quantitation of Muscle Glycogen Synthesis in Normal Subjects and Subjects with Non-Insulin-Dependent Diabetes by 13C Nuclear Magnetic Resonance Spectroscopy
Shulman G, Rothman D, Jue T, Stein P, DeFronzo R, Shulman R. Quantitation of Muscle Glycogen Synthesis in Normal Subjects and Subjects with Non-Insulin-Dependent Diabetes by 13C Nuclear Magnetic Resonance Spectroscopy. New England Journal Of Medicine 1990, 322: 223-228. PMID: 2403659, DOI: 10.1056/nejm199001253220403.Peer-Reviewed Original ResearchConceptsMuscle glycogen synthesisNonoxidative glucose metabolismDiabetic subjectsNormal subjectsGlucose metabolismMuscle glycogenGlycogen synthesisHyperglycemic-hyperinsulinemic clamp studiesTotal body glucose uptakeWeight-matched healthy subjectsNon-insulin dependent diabetesSteady-state plasma concentrationsGlucose uptakeMean glucose uptakeDependent diabetes mellitusDiabetes mellitusInsulin resistanceGlucose disposalPlasma concentrationsHealthy subjectsStudy groupClamp studiesGastrocnemius muscleInsulin actionMean rate